Substituted benzimidazolinethiones

ABSTRACT

Compounds of the following formula   WHEREIN Z is ethylene or propylene; R1 is hydrogen, methyl, ethyl, phenyl, nitrophenyl, benzyl, phenethyl, tolyl or xylyl; R2 is hydrogen, alkyl of from 1 to 5 carbons, benzyl, nitrobenzyl, phenethyl, nitrophenethyl, alkoxycarbonylalkylene wherein the alkoxy radical has from 1 to 5 carbons and the alkylene radical has 1 to 3 carbons, dialkylaminoalkylene wherein the dialkyl radicals have from 1 to 3 carbons and the alkylene radical has 2 or 3 carbons, alkanoyl of from 2 to 18 carbons, benzoyl, a substituted benzoyl wherein said substituent is halogen, alkyl of 1 to 3 carbons or phenyl,   wherein Z and R1 are as defined above,   or   R4 is alkyl of 1 to 3 carbons, phenyl, benzyl or phenethyl; X is O or S; R3 is hydrogen, halogen, nitro, amino, cyano, trifluoromethyl, alkyl of from 1 to 3 carbons, alkoxy of from 1 to 3 carbons, dialkylamino wherein each alkyl radical is from 1 to 3 carbons, alkanoyl of from 2 to 6 carbons, or benzoyl; and n is 1 or 2; are disclosed. These compounds exhibit antiinflammatory activity.

United States Patent Rovnyak et al.

[ Dec. 16, 1975 SUBSTITUTED BENZIMIDAZOLINETHIONES [75] Inventors: George Rovnyak, Hopewell;

Venkatachala L. Narayanan, Hightstown; Rudiger D. Haughwitz, Titusville; Christopher M. Cimarusti, Hamilton, all of NJ.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: July 3, 1974 [21] Appl. No.: 485,419

V [52] US. Cl 260/243 R; 260/306.7 T; 424/246;

I 424/270 [51] Int. Cl. C07D 235/28 [58] Field of Search 260/306'.7 T, 243 R [56'] References Cited UNITED STATES PATENTS 9/1973 Haugwitz et al. 260/306.7 T

OTHER PUBLICATIONS Wagner et al,, Synthetic Organic Chemistry, John 'Wiley, N'.Y., 1953, pp. 645 666-670.

Primary ExaminerR. J. Gallagher Attorney, Agent, or Firm-Lawrence S. Levinson; Merle J. Smith; Stephen B. Davis [57] g ABSTRACT Compounds of the following formula wherein Z is ethylene or propylene; R is hydrogen, methyl, ethyl, phenyl, nitrophenyl, benzyl, phenethyl, tolyl or xylyl; R is hydrogen, alkyl of from 1 to 5 carbons, benzyl, nitrobenzyl, phenethyl, nitrophenethyl, alkoxycarbonylalkylene wherein the alkoxy radical has from 1 to 5 carbons and the alkylene radical has 1 to 3 carbons, dialkylaminoalkylene wherein the dialkyl radicals have from 1 to 3 carbons and the alkylene radical has 2 or 3 carbons, alkanoyl of from 2 to 18 carbons, benzoyl, a substituted benzoyl wherein said substituent is halogen, alkyl of l to 3 carbons or phenyl,

wherein Z and R are as defined above,

0 low.

11 Claims, No Drawings dialkylaminoalkylene wherein each alkyl radical has 1 1 wherein Z and R are as defined above:

'' SUBSTITUTED BENZIMIDAZOLINETHIONES BACKGROUND OF THE INVENTION -i R The prior art discloses the use of a substituted benor: zimidazolinone compounds as antiinflammatory agents X as note US. Pat. No. 3,813,409 issued on May 28. ll 1974. Surprisingly, it has been discovered that the cor- T' responding sulfur containing compounds are also use- R is alkyl on to 3 carb0n5- P y y or P ful as antiinflammatory agents and that it is possible to y prepare such compounds despite the greater nucleo- O or philicity of Sulfur over nitrogen. R" is hydrogen, halogen. nitro, amino, cyano. trifluo- This invention relates to new compounds of the for-' romethyb alkyl of from 1 to 3 b alkoxy of from mula: i l to 3 carbons, dialkylamino wherein each alkyl radical 2 5 is from 1 to 3 carbons, alkanoyl of from 2 to 6 carbons, (I) F or benzoyl.

N S n is one or two. 0 l I 1 The compounds of formula I having a basic substitu- I ent, for example, where R is dialkylaminoalkylene or 3 30 R? is amino or dialkylamino form physiologically acceptable acid-addition salts with inorganic and organic acids. These acid-addition salts frequently provide useful means for isolating the products from reaction mixwhi'ch fl tures by forming" the salt in a medium in which it is ex 1 I an ammatory insoluble. The free base may thenbe obtained by neu- Z represents ethylene or propylene.

R represents hydrogen, methyl, ethyl, phenyl, nitrophenyl, benzyl, phenethyl, tolyl or xylyl.

R is hydrogen; alkyl of l to 5 carbons, e.g. methyl, ethyl, n-propyl, i-propyl, t-butyl, e'tc.; benzyl; nitrobenzyl; phenethyl; nitrophenyl; alko'xycarbonylalkylene wherein the alkoxy radical has from 1 to 5 carbons, e.g. methoxy, i-propoxy, t-butoxy, etc, and the alkylene tralization, e.g., with a base such as sodium hydroxide. Then any other salt may again be formed from the free base and the appropriate inorganic acid. Illustrative are the hydrohalides, especially the hydrochloride and hydrobromide' which are preferred. sulfate, nitrate, phosphate, tartr'ate, maleate, fumarate. citrate, succinate, methanesulfonate, benzenesulfonate, toluenesulradical has 1 to 3 carbons, e.g. CH -(CH fonate and the like 2 8 I I DETAILED" DESCRIPTION OF THE INVENTION Compounds of formula I where R is hydrogen are prepared from the appropriate 2-(o-aminoanilino)-2- thiazoline of formula ll by heating with carbon disulfide in. alcohol, or by the action of thiophosgene in chloroform, or by heating with potassium ethyl xanthate (Van to 3 carbons and the alkylene radical has 2 or 3 car- Allan et al., Organic Syntheses, Collective Vol. 4. p. ;bons; alkanoyl of from 2 to 18 carbons; benzoyl; substi- 569-570).

n R NH nlw (II) L (III) tuted benzoyl Wherem 531d substituent is halogen, alkyl The substituted benzimidazole of formula III may exist of 1 to 3 s or P y in a tautomeric form wherein a hydrogen atom is atk tached to the sulfur atom and the double bond is endo- N/ s cyclic.

\ The 2-(o-aminoanilino)-2-thiazolines of formula ll L are prepared by reacting o-phenylenediamine of formula IV with an haloalkylisothiocyanate of formula V.

NH g 2 2 R 3 n NH halo-2|;NCS (R O iv) (v) (11) K Due to the greater nucleophilieity of S over N it would be expected that the reaction of compounds of formula lll with electrophiles would result in addition occurring at the S atom and not at the N atom. How

ever. it has been discovered that by employing certain.

conditions the reaction will occur at the N atom. These conditions involve the use of a non-polar aprotic solvent and either a weak base or the absence of base. Suitable non-polar aprotic solvents include aromatic hydrocarbons such as benzene. toluene and xylene. ketones such as methyl ethyl ketone, esters such as ethyl acetate, and ethers such as l,2-dimethoxyethane glyme) and bis( 2-methoxyethyl )ether (dig'lyme Suitable weak bases include amines such as pyridine, triethylamine, N.N-dimethylaniline and N-ethylpiperidine.-

Compounds of formula I where R is alkyl. benzyl, nitrobenzyl, phenethyl and nitrophenethyl are prepared -by reacting the substituted benzimidazole of formula ll with the appropriate alkyl halide; benzyl halide. phenethyl halide, etc., at a molar ratio of from about 1:1 to about 1:3 at a temperature of from about 25C to, about l50C for about 0.5 hours to about 24 hours in the presence of a non-polar aprotic solvent and weak base or absence of base as defined above.

are prepared by reacting thesubstituted benzimidazole of formula III with a haloalkylisothiocyanate of formula V under these conditions in the presence of a non-polar aprotic solvent and weak base as defined above.

' Compounds of formula I where R is alkanoyl, benzoyl, substituted benzoyl. alkoxycarbonylalkylene, dialkylaminoalkylene. alkoxycarbonyl, phenoxycarbonyl, benzyloxyc'arbonyl. or Z-phenyl ethoxycarbonyl are prepared by treating the substituted benzimidazole of formula [II with the appropriate halo-R at a molar ratio of from about 1:1 to about 1:15 at a temperature of from about 5C to about 120C for about 0.25 to about 8 hours in the presence of a non-polar aprotic solvent and weak base or absence of base as defined above.

Compounds of formula I wherein R is a substituted urea or thiourea are prepared by reacting the substituted benzimidazole of formula III with a compound of formula (VI) R N=C=X NAS U L l RI 4 can be prepared by treating mercaptobenzimidazoles of formula v I (VII) erably performed in the presence of a strong base as sodium hydride. A mixture of several products is formed from which the compounds of formula I where R is hydrogen and where R is NAS Z can be separated by either crystallization or chromatography.

The mercaptobenzimidazoles of formula VII are obtained by known methods from the o-phenylenediamines of formula IV, as for example, by heating with carbon disulfide in alcohol, by the action of thiophosgene in chloroform, orby heating with potassium Xanthate (Van Allan et al.. supra).

The preferred compounds are those wherein R is hydrogen; n is one; R is hydrogen, halogen, nitro, or alkyl of l to 3 carbons; and R is hydrogen benzyl, alkyl of l to 3 carbons, (CH N(CH wherein R is alkyl of l to 3 carbons or phenyl and X is O or S.

The most preferred compounds are those wherein Z is ethylene; R is hydrogen, methyl or Cl, especially hydrogen; and R' is hydrogen.

The compounds of this invention are useful as antiinflammatory agents and are effective in the prevention and inhibition of granuloma tissue formation in warm blooded animals. and may be used. for example, in a manner similar to phenylbutazone or indomethacin. They may be used to decrease joint swelling, tenderness, pain and stiffness in mammalian species. e.g., in conditions such as rheumatoid arthritis. The compounds of this invention or a physiologically acceptable acid-addition salt thereof as described above may be compounded according 'to accepted pharmaceutical practicefor administration orally or by injection. Suitable oral dosage forms are tablets, capsules. exixirs or powders, while solutions or suspensions are suitable for.

injection. The quantity administered may be from about 25 mg. to about 2 gm. per day, and preferably A solution of 7.8 g. 0.07 mole) of o-phenylenedia mine and 11 1 .9 g. (0.07 mole) of 2-bromoethyl isothiocyanate in 150 ml. of dry glyme is stirred at room ternperature for one hour. The solution is decanted and the remaining viscous oil is taken up in water. basified with K CO and extracted with warm CHCI The combined Cl-lCl extracts are washedwith water and cooled in an ice-bath. The precipitated crystals are collected by filtration and dried yielding 6.6 g. of 2-(0- aminoanilino)-2-thiazoline. Recrystallization from CHCI yields an analytical sample, m.p. 165-l67. b) 1-( 4,5 -Dihydro-2-thiazoly1)- l ,3-dihydro-2fl-benzimidazole-Z-thione A solution of 7.0 g. (0.04 mole) of 2-(0- aminoanilino)-2-thiazoline;from part (a), l 1.2- g. (0.15

mole) of carbon disulfi de "arid 2.8g. (0.05 mole) of' KOH in 70 m1. of ethanol and ml. of water is refluxed for five hours. After-the reaction mixture is cooled, hair-like crystals are formed in'the flask. These crystals are collected by filtration and washed with diethyl ether' yielding 2.4 g. of 1'-(4,5-dihydro-2- thiazoly1)-1 ,3-dihydro-2ljbenzimidazole-2-thione; m.p. 18 818 9. Alternatively: c. l-(4.5-Dihydro-2 thiazolyl)-l,3-dihydro-2fi-benzimidazole-2-thione a A solution of 7.6 g. (0.066 mole) of thiophosgene in 150 ml. of glyme and asolu'tion of 12.1 g. (0.12 mole) of triethylamine in 150 ml. of glyme are added simultaneously over 1.5 hours to a solution'of 11.6 g. (0.06 mole) of 2-(o-aminoanilino)-2-thiazoline'from part (a) in 200 ml. of glyme at a temperature of 25. The resulting solution is then stirred at 40 for 2.5 hours. The solids are removed by filtration. The filtrate is concentrated in vacuo' and the residue is dissolved in 600 ml. of Cl-lCl and washed with 10% HCl, 10%Na1-1CO and water. The product is purified by extracting into aqueous NaOH; washing theaqueous extract with CHCl and precipitating with concentrated HCl. The precipitate is crystallized from aqueous methanol yielding about 8.0 g. (60%) of 1-(4,5-dihydro-2-thiazolyl)-1,3- dihydro-Zfi-bnzimidazole-Z-thione; m.p. l87189.5.

EXAMPLETZ -1- 5.6-Dihydro-4l;l- 1 ,3-thiazin-2-yl -i ,3 -dihydro-2l;lbenzimidazole-Z-thione a. N-( 5,6-dihydro-4ljl ,3-thiazin-2-yl )o-phenylenediamine I A solution of 7.8 g. (0.07 mole) of o-phenylenediamine and 12.6 g. (0.07 mole) of 3-bromopropylisothiocyanate in 150 ml. of dry glyme is stirred at -room 6. temperature for one hour. The solvent is decanted and the remaining viscous oil is taken up in 200 ml. of water. basified with solid K CO and extracted three times with 200 ml. of CHCl The CHClg extracts are washed with water. combined. dried (CaCl and concentrated on a steam bath to approximately 300 ml. N-( 5,6-dihydro-4H-l .3-thiazin-2-yl )o-phenylenediamine is obtained upon cooling the CHCl solution. b. l-( 5 .6-Dihydro-4Lll ,3-thiazin-2-yl l .3-dihydro- 2l;l-benzimidazole-2-thione A solution of 2.53 g. (0.22 mole) of thiophosgene in 50 ml. of glyme and a solution of 4.45 g. (0.44 mole) of triethylamine in 50 ml. of glyme are added simultaneously over 1.5 hours to a solution of 4.14 g. (0.2 mole) of N-( 5 6-dihydro-4l -!-l ,3-thiazin-2-yl )ophenylenediamine from part (a) in ml. of dry glyme at 25. The reaction mixture is stirred an additional 3 hours at 40. After cooling. the solids are removed from the solution by. filtration and the filtrate is concentrated in vacuo. The viscous residue is dissolved in CHCl and washed with 10% HCl, 10% NaHCQ, and water. The product is extracted into N aqueous NaOH, from which it is recovered by acidification with concentrated HCl. The precipitate, thus obtained, is crystallized from aqueous ethanol yielding l-(5.6-dihydro- 4l;l-l,3-thiazin-2-yl)-1,3-dihydro-2li-benzimidazole-2- thione.

EXAMPLES 3-10 Following the procedures of the previous examples but employing the haloalkylisothiocyanate shown in column A the product shown in column B is obtained.

Col. A

-continued EXAMPLE 1 l l-(4,5-Dihydro-2-thiazolyl)-1.3-dihydro-2fl-benzimidazole-Z-thione and l .3-bis(4.5-dihydro-2-thiazolyl)-1,3-dihydro-2fl-benzimidazole-Z-thione 1.8 g. (0.08 mole) of sodium hydride is added with stirring to a solution of 3.8 g. (0.03 mole) of 2-mercaptobenzimidazole in 200 ml. of dry glyme. After the evolution of hydrogen ceases (approximately 1.5 hours). 6.1 g. (0.05 mole) of 2-chloroethyl isothiocyanate is added; and the resulting mixture is refluxed for three hours. The mixture is cooled and the solvent removed by distillation in vacuo. The resulting residue is washed with water, filtered and dried, yielding 6.0 g. of crude product. Fractional crystallization from ethanol yields the titled compounds.

The l.3-bis(4,5-dihydro-2-thiazolyl )-l .3-dihydro- ZH-benzimidazole-Z-thione has the lowest solubility in ethanol. Two recrystallizations from ethanol yields 0.5 g.; m.p. l76l77.

The 1 -(4,5-dihydro-2-thiazolyl)-1,3-dihydro-2flbenzimidazole-Z-thione has the highest solubility in ethanol. After it is isolated, it is then recrystallized from CH CN yielding 0.4 g.; m.p. l83l85.

EXAMPLE 12 l-(4.5-Dihydro-2 thiazolyl)-1,3-dihydro-5(or 6 )-methyl-2l;l-ben zimidazole-Z-thione. A solution of 6.85 g. (0.0416 mole) of 2-mercapto-5- methyl-benzimidazole [prepared by the general 8 method of Van Allan et al.. Org. Syn.. Coll. Vol. 4. p. 569 1963 m.p. 285292] in 270 ml. of dry glyme is stirred under nitrogen at room temperature with 4.05 g. (0.0955 mole) of 57% sodium hydride dispersion in mineral oil. After 1.5 hours. 10 g. (0.0832 mole) of -2-chloroethyl isothiocyanate is added and the slurry is refluxed for three hours. cooled. and the solvent removed in vacuo. The residue is treated with methanol to decompose unreacted hydride and the methanol is removed in vacuo. The resulting oil is triturated with hexane (hexane discarded) and the oil is partitioned between chloroform and water containing a slight excess of acetic acid. The chloroform solution is dried and the solvent removed in vacuo yielding 14.5 g. of crude product. A solution of 1 1.5 g. of this solid in 1:1 chloroform-hexane is chromatographed on a 225 g. alumina (neutral. activity lll) column. Elution with chloroform-hexane mixtures and then chloroform yields 4 g. of TLC pure material. Recrystallization from chloroform-hexane yields 2.4 g. of l-(4,5-dihydro-2- thiazolyl l ,3-dihydro-5 or 6 )-methyl-2fl-benzimidazole-2-thione; m.p. l97l99.

EXAMPLE l3 5( or 6)-Chlorol 4,5-dihydro-2-thiazolyl l ,3-dihydro-2H- benzimidazole-Z-thione A solution of 7.7 g. (0.041 mole) of 5-chlorobenzimidazole-Z-thione in 270 ml. dry glyme is stirred under nitrogen and 4.05 g. (0.0955 mole) of 57% sodium hydride dispersion in mineral oil is added. After stirring at room temperature for 1.5 hours. 12.5 g. (0.1035 mole) of 2-chloroethyl isothiocyanate is added and the reaction mixture is refluxed overnight. The solvent is removed in vacuo and the residue is triturated with methanol. After removal of the methanol in vacuo, hexane is added and removed by decantation. The gummy residue is partitioned between chloroform and water. The chloroform extract is dried with sodium sulfate and evaporated in vacuo yielding 3.7 g. of crude product. This solid material is dissolved in chloroform and chromatographed on an g. alumina (neutral. activity ll) column. Elution with chloroform yields 3.0 g. of TLC pure product. Crystallization from methanol yields 2.0 g. of 5(or 6)-chloro-1-(4,5-dihydro-2- thiazolyl l ,3-dihydro-2l-j-benzimidazole2-thione; m.p. 248250.

EXAMPLE l4 1-( 4 ,5-Dihydro-2-thiazolyl 1 ,3-dihydro-5(or 6 )-nitro-2fl-benzimidazole-2-thione 9.75 g. (0.05 mole) of 5-nitro-benzimidazole-2- thione is added, portionwise, at room temperature to a stirred slurry of 1.5 g. (0.06 mole) of sodium hydride in 400 ml. of dry glyme. After the evolution of hydrogen ceases, 7.25 g. (0.06 mole) of 2-chloroethyl isothiocyanate in 200 ml. of dry glyme is added. The resulting mixture is heated at reflux temperature for three hours. The mixture is cooled and the solvent is removed in vacuo. The residue is dissolved in CHCI and washed with 10% HC1 and twice with water. The organic fraction is dried (CaCl treated with charcoal and concentrated in vacuo. The 1-(4,5-dihydro-2-thiazolyl)- l ,3-dihydro-5(or 6 )-nitro-2lj-bnzimidazole-Z-thione is obtained by chromatography on alumina (neutral.

activity 1) and elution with cyclohexane-chloroform.-

ethanol.

EXAMPLES -33 Col. A

VII

III

Ex. 4 5 4 or 7 5 or 6 l5 No NO. 16 Br Br 17 CF, CF. 18 CN J CN I9 C.,H,, C. .H,, 20 t-C,H,, I t-C H,, 2l 0C 0cm, 2: c1 Cl 23 o i c,H o i c,H 7, /CH:| /CH.1 -4 N ,N

u CH C2H c. 25 N 5 N 5 t 0 0 ll 26 c c ii 27 c--c. .i-1 c C. .H,

l0 :0 2s c-i-cn-i, l q-c n,

in ii 29 c c.l-i,, c-cuH O M ii 30 c-cH, C-CH;,

Also, the following disubstituted compounds are obtained.

Col. A Co]. B

Ex. 4 5 e 7 4 s 6 7 31 c1 Cl Cl Cl 32 ocl-i, OCH" ocH ocn 33 CH1, CH CH1, CH

10 Similarly. by following the procedures of Examples 12 to 14 but also substituting for the 2-chloroethylisothiocyanate the haloalkylisothiocyanates of examples 2 to 10. other compounds within the scope of this invention are obtained.

EXAMPLE 34 l-(4.5-Dihydro-2-thiazolyl l .3-dihydro'-3-( phenylmethyl )-2H-benzimidazole-Z-thione A solution of 2.35 g. (0.1 mole) of l-(4,5-dihydro-2- thiazolyl l ,'3-dihydro-2H-benzimidazole-Z-thione from example 1, L88 g. (().l 1 mole) of benzyl bromide and 0.2 ml. (0.25 mole) of pyridine in 50 ml. of dry toluene is heated at reflux temperature for 16 hours. The reaction mixture is cooled. washed with N sodium hydroxide. water, and saturated brine, dried (CaCL) and concentrated in vacuo. The l-(4.5-dihydro-2- thiazolyl l ,3-dihydro-3-( phenylmethyl )-2fl-benzimidazole-Z-thione is obtained by crystallization from acetone-hexane.

EXAMPLE 35 l-(4.5-Dihydro-2-thiazolyl l ,3-dihydro-3-( l-oxooctadecyl )-ZhLbenzimidazole-Z-thione A solution of 3.32 g. (0.1 1 mole) of stearoyl chloride in 25 ml. of dry toluene is added to a stirred solution of 2.35 g. (0.1 mole) of l-(4.5-dihydro-2-thiazolyl)l.3- dihydro-2lj-benzimidazole-2-thione from example 1 and 0.2 ml. (0.25 mole) of pyridine in 25 ml. of dry toluene at 0 to 5. The reaction mixture is stirred at 0 to 5 for l hour'and is then heated at reflux temperature for 3 hours. The reaction mixture is cooled. washed with N sodium hydroxide. water, and saturated brine, dried CaCl and concentrated in vacuo. The l-( 4,5-dihydro-2-thiazolyl l .3-dihydro-3-( l-oxooctadecyl)-2l:l-benzimidazole-2-thione is obtained by crystallization from aqueous ethanol.

EXAMPLES 36-68 Following thesprocedures of Examples 34 and 35 but substituting for the benzyl bromide and stearoyl chloride the compounds listed below in column A, there are obtained the compounds of the following formula wherein R is the radical listed in column B:

-continued -continued lix. Col. A Col. 1; E.\. (.ol. A Col. B

ll 5f can o-cm A c- 0cm,

t I 40 ():N CHI .C| (.'H;, --NO. 57

ll ll 41 CH CH Br CH2CH. 58 -CH2OCCI -C()CH.

. 3 H 42 0: --C,H'.-CH2Br C C ot 5 s9 (CH. .-o cc| -CO(CH- -)2- CH CH, 60 J\N CH..)..CI CH..)-.-N l u 43 SCN(CH- -);,Cl -c CH\ CH N 2O 61 CHHT/ N(C 2): Cl (C :zl:| C"H7 0 0 g ll 5 62 CHO CH- .Br CH- .C(-)OCH;. 44 SCNCH CHCH-Jh -c' CH3 63 CH;,OC(CH. Cl (CH:)2 COCH;, H3 O O O 0 64 C- .H -,OC(CH- v): Bf -(CH- OC:H7 y. u o O 45 u -c ll ll 65 5 |i -l- (CH- )2- -OC -,H,| ii a r 0 0 66 C. .H,-,COBr -gc H, 1 ll @T 67 CH C0Br IC|CH:,

o i? H 68 CH;,(CH. ,),COCI (CH CH 47 Br -CLCI -C -Br Similarly by following the procedures of Examples 34 and 35 but substituting for the l-(4,5-dihydro-2- Br 0 0 Br thiazolyl)-l,3-dihydro-2Ll-benzimidazole-2-thione the H product of Example 2 or Examples 3 to 10, other com- 43 pounds within the scope of this invention are prepared.

' EXAMPLE 69 I Q 0 c1 3-(4,5-Dihydro-2-thiazolyl)-2,3-dihydro-N-phenyl-2- u thioxo-lH-benzimidazole-l-carboxamide A solution of 1.17 g. (0.05 mole) of l-(4,5-dihydro- Z-thiazolyl l ,3-dihydro-2l;l-ben'2imidazole-2-thione from Example 1 and approximately 2 mlwof phenyl 0 cl isocyanate (0.10-0.15 mole) in 100 ml. of dry toluene 5U ,ll is heated overnight at reflux temperature. The solution is cooled, diluted with one volume of hexane, and a 0 precipitate consisting mainly of unreacted starting material is removed by filtration. The filtrate is washed 51 Cl C' with dilute aqueous Na CO and water. dried (CaCland concentrated in vacuo. The residue is triturated 0 with hexane and the solid that forms is collected and 52 H1C COC| crystallized from acetone-hexane yielding 0.45 g. of

' I 3-(4,5-dihydro-2-th1azolyl-Z,3-dihydro-N-phenyl-2-thi- O 0 oxo-lLl-benzimidazole-l-carboxamide; m.p.'l38140 53 H l EXAMPLES 70-76 I 1 Following the procedure of Example 69 but substitut- O 0 ing for the phenyl isocyanate the the compounds listed 54 CHRCFCBT below in column A, there is obtained respectively the o 0 compound of the following tormula wherein R- 15 the 55 CLIHSO QCI ll radical listed in column B:

Similarly, by following the procedure of Example 69 but also substituting for the l-( 4,5-dihydro2- thiazolyl )-1 ,3-dihydro-2H-benzimidazole-Z-thione the products of Examples 2 to 10, other compounds within the scope of this invention are obtained.

EXAMPLE 77 (or 6)-Aminol -(4,5-dihydro- Z-thiazolyl l ,3-dihydro-2fibenzimidazole-2thione, hydrochloride 2.8 g. (0.01 mole) of l-(4,5-dihydro-2-thiazolyl)-1,3- dihydro-5(or 6 )-nitro-2Ll-benzimidazole-2-thione from Example 14 in 200 ml. of ethanol is reduced with hydrogen over Raney Nickel catalyst at a pressure of 3 to 4 atmospheres. The catalyst is removed by filtration and the filtrate is reduced in vacuo to a volume of about 50 ml. and then saturated with dry l-lCl. Upon standing, the hydrochloride precipitates and is purified by crystallization from ethanol yielding the 5(or 6)- amino- 1 4,5-dihydro-2-thiazolyl )-l ,3-dihydro-2Ll benzimidazole-2-thione, hydrochloride.

What is claimed is:

l A compound of the formula:

N 5 l RI wherein R and Z are as defined above.

X is oxygen or sulfur; R is alkyl of l to 3 carbons, phenyl, benzyl, or phenethyl; R is hydrogen, halogen, nitro, amino, cyano, trifluoromethyl, alkyl of l to 3 carbons, alkoxy of l to 3 carbons, dialkylamino wherein each alkyl is of l to 3 carbons, alkanoyl of 2 to 6 carbons, or benzoyl; and n is one of two;- and when R is dialkylaminoalkylene or R is amino or dialkylamino the pharmaceutically acceptable acid-addition salts.

2. The compounds of claim 1 wherein R is hydrogen; R is hydrogen, alkyl of l to 3 carbons wherein Z is ethylene or propylene, benzyl, -(CH M ab,

R is alkyl of l to 3 carbons or phenyl, R is hydrogen,

halogen, nitro, or alkyl of l to 3 carbons; and n is one.

3,9 26,982 1:5 16 3. The compound of claim 2 wherein Z is ethylene. 9. The compound of claim 3 wherein R is 4. The compound of claim 3 wherein R is hydrogen; and R is hydrogen. CH or Cl.

5. The compound of claim 4 wherein R is hydrogen. 5 6. The compound of claim 4 wherein R" is CH;,. CNH 7. The compound of claim 4 wherein R is Cl. 8. The compound of claim 3 wherein R is 10. The compound of claim 2 wherein Z is propylene. A 11. The compound of claim wherein R- IS hydro- .s. gen.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF coREer PATENT N0. 1 ,9 2 DATED December 16, 1975 lN\/ ENTOR(S) G. Rovnyak et al.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Under inventors, "Rudiger D. Haughwitz" should read -Rudiger D. Haugwitz-.

Col. 3, line 19, "formula II" should read -formula III-.,

Col. 5, line 5, "exixirs" should read --eliXirs-.

En'gne this [SEAL] fourth ay of May 1976 Arrest:

RUTH C. MASON C. MARSHALL DANN Arlest' mg Ojjuer mmmssunwr 0] PUIE'IIS and Trademarks 

1. A COMPOUND OF THE FORMULA:
 2. The compounds of claim 1 wherein R1 is hydrogen; R2 is hydrogen, alkyl of 1 to 3 carbons
 3. The compound of claim 2 wherein Z is ethylene.
 4. The compound of claim 3 wherein R2 is hydrogen; and R3 is hydrogen, CH3 or Cl.
 5. The compound of claim 4 wherein R3 is hydrogen.
 6. The compound of claim 4 wherein R3 is CH3.
 7. The compound of claim 4 wherein R3 is Cl.
 8. The compound of claim 3 wherein R2 is
 9. The compound of claim 3 wherein R2 is
 10. The compound of claim 2 wherein Z is propylene.
 11. The compound of claim 10 wherein R2 is hydrogen. 